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IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available data...

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Autores principales: Kalya, Manasa, Kel, Alexander, Wlochowitz, Darius, Wingender, Edgar, Beißbarth, Tim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239365/
https://www.ncbi.nlm.nih.gov/pubmed/34211498
http://dx.doi.org/10.3389/fgene.2021.670240
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author Kalya, Manasa
Kel, Alexander
Wlochowitz, Darius
Wingender, Edgar
Beißbarth, Tim
author_facet Kalya, Manasa
Kel, Alexander
Wlochowitz, Darius
Wingender, Edgar
Beißbarth, Tim
author_sort Kalya, Manasa
collection PubMed
description Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated.
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spelling pubmed-82393652021-06-30 IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme Kalya, Manasa Kel, Alexander Wlochowitz, Darius Wingender, Edgar Beißbarth, Tim Front Genet Genetics Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated. Frontiers Media S.A. 2021-06-15 /pmc/articles/PMC8239365/ /pubmed/34211498 http://dx.doi.org/10.3389/fgene.2021.670240 Text en Copyright © 2021 Kalya, Kel, Wlochowitz, Wingender and Beißbarth. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Kalya, Manasa
Kel, Alexander
Wlochowitz, Darius
Wingender, Edgar
Beißbarth, Tim
IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
title IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
title_full IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
title_fullStr IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
title_full_unstemmed IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
title_short IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
title_sort igfbp2 is a potential master regulator driving the dysregulated gene network responsible for short survival in glioblastoma multiforme
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239365/
https://www.ncbi.nlm.nih.gov/pubmed/34211498
http://dx.doi.org/10.3389/fgene.2021.670240
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